Introduction

Mirikizumab (MIRI) is a humanized anti-interleukin-23-p19 monoclonal antibody (mAb) approved for ulcerative colitis (UC) with demonstrated efficacy for Crohn’s disease (CD) in Phase 2 (AMAG, NCT02891226) and Phase 3 (VIVID-1, NCT03926130) trials.^1,2 This analysis characterized MIRI pharmacokinetic (PK) properties and exposure-response (ER) relationships in adults with moderately to severely active CD using data from 2 trials.

Aims & Methods

Patients received 12-week MIRI induction (200, 600 or 1000 mg [AMAG] or 900 mg [VIVID-1] intravenously [IV] every 4 weeks [Q4W]), followed by MIRI maintenance (200, 600 or 1000 mg IV [AMAG], or 300 mg administered subcutaneously (SC) [AMAG and VIVID-1] Q4W) up to Week (W)52. PK parameters were estimated by non-linear mixed-effects modeling. Covariate effects on MIRI exposure were evaluated using simulation-based estimations. The exposure efficacy model included data from participants who had model-predicted average drug concentration during multiple dosing. Clinical efficacy at W12 was compared with AMAG graphically and models were conducted on primary endpoints. ER for patients achieving endoscopic response by Simple Endoscopic Score for CD (SES-CD) at W12 and W52 were assessed using logistic regression models.

Results

MIRI PK was best described by a linear two-compartment model with first-order absorption. Population (PopPK) model-estimated parameters were consistent across AMAG and VIVID-1 (Table). AMAG indicated a near-maximal efficacy for doses between 600 and 1000 mg IV for endoscopic response by SES-CD at W12, suggesting that 900 mg IV in VIVID-1 would produce near-maximal effect for W12 endpoints. Linear relationships between exposure and W12 endoscopic response by SES-CD best described observed data in VIVID-1. In AMAG, model-based analyses of the relationships between exposure and W52 efficacy measures showed no ER trend across MIRI maintenance doses, supporting 300 mg SC Q4W for VIVID-1 Maintenance Period. Linear relationships between exposure and endoscopic response by SES-CD on a logistic scale best described observed data in VIVID-1 at W52. None of the covariates evaluated in PK or ER modelling were considered clinically relevant.

	CL (L/h)	Albumin effect on CL	Q(L/h)	BLBW effect on CL and Q	Vcc (L)	Vpc (L)	BLBW effect on Vc and Vp	Fd %	BL BMI effect on F
VIVID-1 Population estimate [95% CIa, % SEE]	0.0197b [0.0179 to 0.0230, 4.53]	-0.0200 [-0.0228 to -0.0173, 7.25]	0.00921b [0.00529 to 0.0252, 26.6]	0.268 [0.150 to 0.378, 23.1]	2.78b [2.71 to 2.82, 0.978]	1.61b [1.13 to 2.85, 16.5]	0.445 [0.372 to 0.517, 9.53]	38.8 [33.8 to 45.8, 5.62]	-0.0354 [-0.0469 to -0.0263, 13.9]
AMAG Population estimate [95% CIa, % SEE]	0.0217e [0.0203 to 0.0306, 6.27]	-0.754 [-0.976 to -0.598, 12.0]	0.00884f [0.00605 to 0.202, 42.3]	0.538 [0.348 to 0.745, 19.7]	3.31f [3.08 to 3.45, 2.21]	1.75f [1.49 to 5.67, 18.2]	0.543 [0.330 to 0.721, 18.1]	0.334g [0.296 to 0.445, 8.44]	-0.0318 [-0.0434 to -0.0206, 18.2]
aEstimated using bootstrap; bCL,i=CL*(BLBW/65.0)0.268*(1+Albumin-44.57)*0.02*(BL CRP/7.41)0.0853; Q,i= Q*(BLBW/65.0)0.268; cVc,i=Vc*(BLBW/65.0)0.445; Vp,i=V3*BLBW/65.0)0.445; dEstimate is on the logit parameter for bioavailability; eCL,i=CL*(BLBW/71.8)0.538*(BL SES-CD/12)0.227*(Albumin/44.0)-0.754; fCL,i=CL*(BLBW/71.8)0.538; Vc,i=Vc*(BLBW/71.8)0.543; Vp, i= Vp*BLBW/71.8)0.543; gF,i= F*[1+(VL BMI – 24.75)*-0.0318]
BL=baseline; BW=body weight; BMI=body mass index; CI=confidence interval; CL=clearance; CV=geometric coefficient of variation; F=bioavailability; i=individual; L/h=Liters per hour; Q=intercompartmental clearance; SEE=standard error of the estimate; SES-CD=Simple Endoscopic Score for CD; Vc=volume of distribution of the central compartment; Vp=volume of distribution of the peripheral compartment

Conclusion

MIRI PK characteristics in AMAG and VIVID-1 were consistent with UC studies and typical of mAbs.³ ER analyses showed MIRI induction dose of 900 mg IV at W0, W4, and W8 followed by maintenance dose of 300 mg SC Q4W resulted in near-maximal efficacy in VIVID-1. These findings support MIRI dosing regimen proposed for patients with moderately to severely active CD. PK and ER data suggested that no adjustments based on patient factors are warranted.

References

1. Sands B, et al. Gastroenterology. 2022;162:495-508.
2. Ferrante M, et al. J Crohns Colitis. 2024;18:i7-i9.
3. Chua L, et al. Clin Pharmacokinet. 2023;62:1479-1491.

Disclosure

L. Chua, Y. Otani, F. Durand and X. C. Yang are current employees of and shareholders: Eli Lilly and Company; S. Friedrich is a former employee of: Eli Lilly and Company.

Introduction

Irritable bowel syndrome is one of the most common Disorders of gut-brain interaction, with diarrhea being the predominant subtype. At present, there are limited drugs for effective management of irritable bowel syndrome.
Compound glutamine entersoluble capsules are composed of traditional chinese medicine formulas Sijunzi Tang and L-glutamine. The Sijunzi Tang, which has been used in traditional complementary and alternative integrated medicine, has been used for the treatment of irritable bowel syndrome for many years. However, there is a lack of evidence from modern evidence-based medicine, its clinical efficacy and safety need to be confirmed. L-glutamine has the function of repairing damaged intestinal mucosa.

Aims & Methods

This study performed a multicenter randomized double-blind placebo-controlled withdrawal trial to explore the effectiveness and safety of compound glutamine entersoluble capsules in the treatment of diarrhea predominant irritable bowel syndrome.
The selected participants received the investigational drug for four weeks during the first single arm stage. The responding participants were randomly assigned to the compound glutamine entersoluble capsules and placebo groups in a 1:1 ratio for another 4 weeks.
The primary efficacy endpoint of the study was the response rate of both the improvement in abdominal pain and bowel movements after treatment in randomized controlled trial subjects (50% of the treatment course met the requirement of at least 30% improvement in abdominal pain severity (NRS pain score) and a reduction of at least 50% in bowel movement days for Bristol 6 or 7 types).

Results

A total of 558 subjects in 22 centers, of which 493 subjects were successfully screened and entered the placebo introduction period. During the placebo introduction period, there were a total of 493 subjects, of which 481 subjects were successfully rescreened and entered the single arm period. 437 subjects entered the randomized controlled trial period and were randomly divided into a treatment group of 217 subjects and a placebo group of 220 subjects.
For the primary efficacy endpoint, the number of response cases in the experimental group and placebo group were 114 (54.55%) and 89 (41.20%), respectively (P=0.0059). For secondary efficacy endpoints: (1) The number of improvements in NRS pain scores in the experimental group and placebo group were 138 (66.03%) and 107 (49.54%), respectively (P=0.0006); (2) The number of improved bowel movements in the experimental group and placebo group were 157 (75.12%) and 118 (54.63%), respectively (P<0.0001); (3) The median (quartile) relative baseline change of IBS-SSS scale in the experimental group was -47.00 (-97.00, -14.00) points; The median (quartile) relative baseline change in the placebo group was -17.00 (-63.00, 16.00) points, and there was a statistically significant difference between the two groups (P<0.0001); (4) The median (quartile) relative baseline change of IBS-QOL in the experimental group was -11.46 (-43.01, 0.00) points; The median (quartile) relative baseline change in the placebo group was -3.57 (-39.43,0.00) points (P=0.0007).
During the randomized controlled trial period, the incidence of all adverse events in the 217 subjects in the trial group was 18.89%, the placebo group was 22.27%, the incidence of TEAEs related to the drug in the trial group was 2.30%, and the placebo group was 3.18%.

Conclusion

Compound glutamine entersoluble capsule can effectively improve the clinical symptoms of diarrhea predominant irritable bowel syndrome with a satisfactory safety.

Introduction

Etrasimod is an oral, once-daily (QD), selective sphingosine 1‑phosphate (S1P)_1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). S1P₁ receptor modulation is believed to reversibly sequester lymphocytes¹; its impact on UC intestinal tissue is unknown.

Aims & Methods

We characterised the impact of etrasimod in inflamed colonic biopsy tissue using ribonucleic acid sequencing (RNA-seq) to examine transcriptional-level impacts on disease, in terms of mucosal barrier inflammatory pathways and immune cell populations. In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients (pts) aged 16–80 years with moderately to severely active UC were randomised 2:1 to etrasimod 2 mg QD or placebo (PBO). Etrasimod treatment effects were characterised by RNA-seq at Week 12 vs baseline (both trials), and in responders achieving clinical remission vs nonresponders. CytoPro (CytoReason) was used for colon-specific cell type deconvolution analysis and single sample Geneset Enrichment Analysis was used for pathway analysis.

Results

At baseline in ELEVATE UC 52/ELEVATE UC 12, colon biopsy samples were available for 245/166 pts receiving etrasimod and 114/84 pts receiving PBO. There were significant reductions in T cell subsets (CD4+, CD8+, helper [Th]1 and Th17), plasma/mature B cell subsets and innate immune cell subsets (monocytes, macrophages, dendritic cells and natural killer cells) in the colon of pts receiving etrasimod (false discovery rate [FDR] < 0.05]); significant changes were not seen among pts receiving PBO. There were also reductions in inflammatory fibroblasts and increases in epithelial cells in the colon of pts receiving etrasimod but not PBO. The change in immune cell populations for responders vs nonresponders at Week 12 was similar to that for etrasimod Week 12 vs baseline. At Week 12, several inflammatory pathways were reduced in responders vs nonresponders to etrasimod; IL-17 signalling was among the most affected (both trials). Nonimmune pathways related to mucosal healing were significantly increased in Week 12 responders.

Conclusion

Decreases in activated immune cell subset and inflammatory signalling pathway changes in responders to etrasimod suggest reductions in local inflammation may contribute to remission and mucosal healing. RNA-seq with cell type deconvolution and pathway analysis contributes to the understanding of etrasimod’s mechanism of action.

References

1. Scott FL et al. Br J Pharmacol 2016; 173: 1778–1792.

Disclosure

BS has received lecture fees from AbbVie, CED Service GmbH, Chiesi, Dr. Falk, Forga Software, Galapagos, IBD Passport, Janssen, Materia Prima, Pfizer Inc and Lilly; consultancy fees from AbbVie, Arena Pharma, Boehringer Ingelheim, BMS, Celgene, CT-Scout, Endpoint Health, Galpagos, Gilead Sciences, Janssen, Landos, Lilly, Pfizer Inc, PredictImmune and PsiCro. RDR is an employee of and holds stock options with Pfizer Inc. CMC, XG and JCW are employees and shareholders of Pfizer Inc. MTA has received consultancy fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celsius, Eli Lilly, Gilead, Janssen, Microba Life Sciences, Pfizer, Prometheus, Prometheus Bioscience, Takeda and UCB Biopharma. SV has received lecture/speaker fees from AbbVie, Dr. Falk Pharma, Ferring, Galapagos, Hospira, Janssen, MSD, Takeda and Tillotts; consultancy/advisory fees from AbbVie, AbolerIS Pharma, Alimentiv, Arena , AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr. Falk Pharma, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, Johnson & Johnson, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer Inc, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance Biopharma, Tillots Pharma AG and Zealand Pharma; grant/research support from AbbVie, MSD, Pfizer Inc, Galapagos, Janssen and Takeda. ID has received consultancy fees, research grants or honoraria from Abbott, AbbVie, Altman, Arena, Athos, Cambridge Healthcare, Celgene/BMS, Celltrion, Falk Pharma, DSM, Ferring, Food Industries Organisation, Galapagos, Genentech/Roche, Gilead, GSK, Hospital for Sick Children, Integra Holdings, Iterative Scopes, Janssen, Mediahuset, Medscape, Neopharm, Nestle, Peer voice, Pfizer, Rafa Laboratories, Sangamo, Sublimity, Takeda, Wilbio. KMR has received grant/research support from Bristol Myers Squibb. HKK has received consultancy fees from Kinevant Sciences and is an employee/shareholder for Uniquity Bio. MG is an employee and shareholder of Pfizer AG. SD has received lecture/speaker fees from AbbVie, Amgen, Ferring Pharmaceuticals Inc, Gilead, Janssen, Mylan, Pfizer and Takeda; consultancy/advisory fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead Sciences, Hospira, Janssen, Johnson & Johnson, MSD, Mundipharma, Pfizer Inc, Roche, Sandoz, Takeda, TiGenix, UCB, and Vifor; holds directorship/ownership for Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele.

Introduction

Both patients and clinicians would benefit from less invasive means than endoscopy for detection of gut inflammation in inflammatory bowel disease (IBD), such as faecal or serological biomarkers.

Aims & Methods

The aim of this study was to investigate the presence of the neutrophilic proteins: calprotectin (CP), myeloperoxidase (MPO), neutrophil gelatinase-associated lipocalin (NGAL) and the eosinophilic protein: eosinophil-derived neurotoxin (EDN) in faecal and serum samples from IBD patients with ulcerative colitis (UC) and Crohn’s disease (CD) in relation to disease activity and intestinal inflammation localization. Their diagnostic potential in IBD was studied using irritable bowel syndrome (IBS) patients as controls.
Faecal (f) and serum (s) samples from 97 IBD (median: 38y, range 18-79y) and 100 IBS (median: 36y, range 18-75y) patients from the outpatient Gastroenterology Clinic, Uppsala University Hospital were included in the study. Active disease was defined as having a Partial Mayo score ≥ 2 (UC) or Harvey-Bradshaw score ≥5 (CD). Disease localization was obtained from patient journals.
CP and EDN were measured by commercial EliA and ImmunoCAP assays, respectively. MPO and NGAL were measured with in-house research assays based on the ImmunoCAP technology. All analyses were done using the automated Phadia 250 instrument.

Results

All four biomarkers were elevated in IBD compared to IBS in faecal samples (p<0.001) and serum (p<0.01), and most biomarkers were also elevated in the separate UC and CD groups (Table 1). Faecal EDN were higher in CD compared to both UC (p=0.016) and IBS.
Table 1. Biomarker levels in UC and CD patients in comparison to IBS patients

	UC N=59	CD N=38	IBS N=100	p-value (UC vs. IBS)	p-value (CD vs. IBS)
fCP	305.8 mg/kg	165.8 mg/kg	16.51 mg/kg	<0.0001	<0.0001
fMPO	3.74 mg/kg	2.42 mg/kg	0.10 mg/kg	<0.0001	<0.0001
fNGAL	7.30 mg/kg	6.78 mg/kg	2.36 mg/kg	<0.0001	<0.0001
fEDN	0.50 mg/kg	1.79 mg/kg	0.29 mg/kg	0.049	<0.0001
sCP	4186 µg/L	4124 µg/L	3037 µg/L	0.0145	ns
sMPO	291.6 µg/L	291.2 µg/L	151.3 µg/L	0.0006	0.0038
sNGAL	240.2 µg/L	239.5 µg/L	162.2 µg/L	<0.0001	0.0004
sEDN	29.07 µg/L	24.54 µg/L	19.4 µ/L	0.0020	ns

Four biomarkers were elevated in active UC vs remission: fCP (610.9 mg/kg vs 45.5 mg/kg, p=0.0180), fMPO (6.84 mg/kg vs 1.30 mg/kg, p=0.0479), sCP (4599 µg/L vs 3128 µg/L, p=0.0194) and sNGAL (298.3 µg/L vs 189.3 µg/L p=0.0012). No association was observed between the biomarkers and disease activity in CD.
Patients with extensive UC had significantly higher levels, compared to patients with left-sided UC, of fCP (851.6 mg/kg vs 148.3 mg/kg, p=0.0135), fMPO (17.67mg/kg vs 2.84 mg/kg, p=0.0493) and fEDN (1.34 mg/kg vs 0.36 mg/kg, p=0.0146). None of the biomarkers were associated with disease localization in CD.

Conclusion

Faecal and serum CP, MPO, NGAL and EDN may be used as diagnostic biomarkers to differentiate patients with IBD from IBS. Our study indicates that fMPO may be used as an alternative to fCP as disease activity marker in UC, and that sCP and sNGAL are promising novel serum markers for disease activity. In addition to the neutrophil markers, fEDN could be of value for characterization of extensive disease in UC patients. The higher fEDN levels in CD compared to UC observed in the present study indicates an important role of activated eosinophils in the clinical manifestation of CD.
The biomarkers MPO, NGAL and EDN measured both in faecal and serum could, in addition to CP, potentially aid in the clinical decision-making in IBD.

Disclosure

H Ekoff, N Rydell and R Movérare are employed by Thermo Fisher Scientific.

Introduction

Mirikizumab, a p19-directed interleukin-23 monoclonal antibody, is efficacious in inducing clinical response at Week(W) 12 and maintaining clinical remission through W52 in patients with moderately-to-severely active Crohn’s disease (CD) as shown in the phase 3 treat-through trial VIVID-1 (NCT03926130).¹ Here, we present analysis of maintenance outcomes through W52 for Patient-Reported Outcome (PRO) clinical responders and nonresponders at W12.

Aims & Methods

The analysis set includes patients randomized to mirikizumab at baseline, who did or did not achieve PRO clinical response at W12 after intravenous (IV) induction treatment (900 mg mirikizumab IV every 4 weeks [Q4W]) before entering subcutaneous (SC) maintenance treatment (300 mg mirikizumab SC Q4W). Descriptive statistics are used to summarize the data, applying nonresponder imputation for missing binary endpoints. As a treat-through study, no rerandomization was applied.

Results

From a total of 551 patients who entered SC maintenance treatment, baseline characteristics of age, duration of CD, and baseline Crohn’s Disease Activity Index (CDAI) were similar between W12 PRO responders (n=402, 73.0%) and W12 PRO nonresponders (n=149, 27.0%). PRO responders at W12 had a higher objective inflammatory burden at baseline (faecal calprotectin, c-reactive protein, and Simple Endoscopic Score-CD), whereas concomitant or prior medication usage was similar between the groups. For W12 PRO responders, SC mirikizumab treatment from W12 to W52 resulted in an increase in CDAI clinical remission from 52.2% to 65.4%, PRO clinical remission from 53.2% to 65.4%, and endoscopic response from 35.1% to 54.7%, respectively (Table 1). Among W12 PRO nonresponders, PRO response was achieved by 39.6% at W16, 45.6% at W20, 44.3% at W24, and 56.4% at W52 with continued mirikizumab SC treatment, while CDAI clinical remission and PRO clinical remission were achieved by 33.6% and 31.5% at W52, respectively. Endoscopic response increased from 30.2% at W12 to 40.3% at W52 among W12 PRO nonresponders (Table 1).

		PRO Nonresponders at W12 (N=149)	PRO Responders at W12 (N=402)
CDAI clinical remission, n (%)a	W12	8 (5.4%)	210 (52.2%)
	W16	16 (10.7%)	208 (51.7%)
	W20	28 (18.8%)	243 (60.4%)
	W24	35 (23.5%)	242 (60.2%)
	W52	50 (33.6%)	263 (65.4%)
Endoscopic response, n (%)a	W12	45 (30.2%)	141 (35.1%)
	W52	60 (40.3%)	220 (54.7%)
aPercentage of response is calculated by n/Nx*100%. CDAI, Clinical Disease Activity Index; PRO, patient-reported outcome

Table 1.

Conclusion

Subcutaneous mirikizumab maintenance treatment over 40 weeks leads to incremental and sustained improvements in rates of clinical and endoscopic response regardless of PRO clinical response status after induction. A substantial proportion of clinical nonresponders at W12 improved early during maintenance treatment suggesting continued treatment with mirikizumab can be beneficial and lead to long-term response.

References

1. Ferrante, Marc et al. Efficacy and safety of mirikizumab in patients with moderately-to-severely active Crohn's disease: a phase 3, multicentre, randomised, double-blind, placebo-controlled and active-controlled, treat-through study. Lancet. 2024;404(10470):2423-2436. doi:10.1016/S0140-6736(24)01762-8